Whilst our laboratory has a broad interest in the pathophysiology of obesity, insulin resistance and type 2 diabetes, this particular research group focuses on the rarer metabolic diseases which are caused by known single gene variants or known genetic regions.

Prader-Willi syndrome

Prader-Willi syndrome (PWS) is one of the most common known genetic obesity disorders; it causes individuals with the disease to have an insatiable appetite, which often leads to the development of morbid obesity. The syndrome has two separate, opposite phases – infants born with PWS find it difficult to feed and are often underweight; then, as children and adults, they eat voraciously and rapidly gain weight if their food intake is not strictly controlled. The transition between the two phases generally takes place around 2-6 years of age. People with PWS have other problems including poor muscle development, sleep disorders and behavioural difficulties, and many also experience co-morbidities such as cardiovascular disease.

There is currently no pharmacological treatment for excessive appetite in PWS. The only way that this appetite can be controlled is through constant vigilance, behavioural restraints and environmental modifications such as locked fridges and cupboards. Many adults with PWS would be able to live more independently if there were effective appetite treatments.

Garvan established the Clinical PWS Research Group in 2006, and has since then become one of the biggest research groups in this field. It has conducted very informative clinical research in several areas of PWS, helping to understand the physiological basis for the insatiable appetite and to develop treatments to combat it, as well as investigating underlying mechanisms of cardiovascular disease.

Our own research has demonstrated that there is no inherent problem in metabolic rate in adults with PWS, suggesting that increased appetite is the main driver of obesity in this disease (Purtell et al., 2015). To investigate appetite, we investigated how hormone released from the gut after eating can influence the balance of hunger and fullness differently in people with PWS compared to healthy people (Purtell et al., 2011). Since these hormone pathways are so important in PWS, we then tested a hormone-like drug and found that a single injection was successful in causing increased fullness in people with PWS, a hugely promising finding (Sze et al., 2011). This published proof-of-principle study has now been taken into the next stage of development towards a therapy for PWS in a clinical trial in the US. We have also identified two things that are related to increased cardiovascular risk in this syndrome: increased low-grade inflammation (Viardot et al., 2010) and a problem in the autonomic nervous system regulating the cardiovascular system (Purtell et al., 2013).

We have several new projects underway in PWS research, working towards understanding how critical low muscle mass is for bone strength as well as understanding the link between eating and inflammation in people with PWS. Importantly, we are commencing a study testing a novel therapy to reduce appetite, testing also for possible benefits to behaviour and cognition. Finding potential treatments for PWS relies heavily on private family donations. Garvan is extremely grateful to those who are enabling us to tackle this challenging area of work.

Monogenic Forms of Diabetes

Diabetes represents a major health and economic burden to Australia. Diabetes can be classified into a number of different types, most common being type 1 and type 2 diabetes. Because genetic testing is not available in Australia, it is estimated that many are wrongly classified into either of these categories, and may actually have an undiagnosed form of monogenic diabetes. These monogenic forms of diabetes are estimated to be up to 5% of all diabetes patients, compared to 10% of type 1 diabetes and 85% of type 2 diabetes. Importantly, these patients require treatments that differ from standard regimens, and if undiagnosed, suboptimal management can lead to worse clinical outcomes. Therefore, introducing affordable genetic testing is essential. Current clinical diagnostic algorithms propose sequential testing of the most likely affected genes by conventional methods, which is slow, expensive, and delivers only rarely a genetic diagnosis. The recent drop in cost of whole genome sequencing (WGS) means that it is now an attractive tool in the diagnosis of patients with mutations in known monogenic disease genes, and also adds an opportunity to identify new disease genes in mutation-negative patients. These new genes could be used to identify subgroups within type 1 or 2 diabetes which have a distinct metabolic defect and might respond differently to the standard medication, enabling us to individualise the treatment for these patients.

The aim of our work is to test the performance of WGS in the diagnosis of monogenic forms of diabetes in a tertiary referral hospital. This will allow us to tailor the treatment of these newly identified patients according to their gene mutations and to prospectively assess whether the genetic diagnosis changes treatment outcomes and health costs over the following 12 months. In mutation-negative patients we will have the opportunity to further explore and identify new genes and variants underlying the yet undiscovered monogenic forms of diabetes or specific subgroups of type 1 and type 2 diabetes patients.

Viardot A, Samocha-Bonet D, Heilbronn LK, Campbell LV. The role of immune activation in insulin sensitive non-diabetic subjects with a strong family history of type 2 diabetes. Abstract at the Annual Scientific Meeting of the Australian Diabetes Society (ADS) & Australian Diabetes Educators Association (ADEA); August 26-28, 2009; Adelaide, South Australia.

Viardot A, Herzog H, Campbell LV. Has gut-derived hormone PYY 3-36 a causative role in hyperphagia and obesity in Prader-Willi syndrome? Abstract at the IPWSO Scientific Conference in Cluj-Napoca, Romania, June 21-22, 2007

Viardot A, Mackay F, Campbell LV. PYY 3-36 Has Anti-Inflammatory Effects on T-Lymphocytes. Is There a Role in Inflammation in Obesity and T2D? Poster at the 89th annual meeting of the Endocrine Society, 2-5 June 2007, Toronto, CA